Slc12a1I299F – mouse mutation mimicks human phenotype (and more)

Type I Bartter syndrome is a rare hereditary recessive human kidney disease with a severe urinary concentration defect due to impaired ion transport capacity of ion transporter NKCC2 in the thick ascending limb of Henle’s loop. The nephropathy is caused by loss-of-function mutations in SLC12A1, the gene coding for the Na+-K+-2Cl− co-transporter NKCC2. A mouse line carrying the mutation I299F in the Slc12a1 gene has been established exhibiting reduced NKCC2 ion transport capacity. It was known already that the Slc12a1I299F mutants exhibit a severe nephropathy highly similar to the late-onset manifestation of the disease in humans, e.g. severe urinary concentration defects, low blood pressure and osteopenia.

NKCC2 is strongly expressed in the kidney. In rodents NKCC2 is also expressed in the gastrointestinal tract, pancreatic beta cells, and specific compartments of the ear, nasal tissue and eye.To examine if further organ systems and/or metabolic pathways are affected by the Slc12a1I299F mutation besides the known kidney defects, mutant mice were systematically screened in the German Mouse Clinic.

The published nephropathy-associated phenotypic alterations like low blood pressure and changes in bone metabolism were confirmed in the screen. Additionally the scientists identified significantly lower body weight and fat content which have not been described before. Furthermore, small additional effects included a mild erythropenic anemia in homozygous mutant males as well as a slight hyperalgesia in homozygous mutant females. If these changes are primary or secondary effects is not clear so far. However, it might be worth keeping the results from the mutant mouse line in mind when treating human patients with Type I Bartter syndrome.